Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted.
Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3 weeks.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在乙醇存在下，阿维A酸通过形成阿维A酰辅酶A转化为依曲替酸。
... In the presence of ethanol the ethyl esterification of acitretin to etretinate proceeds via formation of acitretinoyl-CoA.
IDENTIFICATION AND USE: Acitretin is a keratolytic agent indicated for the treatment of severe psoriasis in adults. Acitretin has been used in a limited number of patients for the management of discoid lupus erythematosus. HUMAN STUDIES: Symptoms of overdose are identical to acute hypervitaminosis A, including headache and vertigo. Lipid elevations were reported in 25-50% of acitretin recipients. Elevations of triglycerides to concentrations associated with fatal fulminant pancreatitis are rare; however, cases have been reported with acitretin. Rare cases of pancreatitis without hypertriglyceridemia also have been reported. The case of a female psoriatic patient with angioedema (without urticaria) due to oral acitretin was reported. Acitretin should be considered as a possible cause of thrombotic stroke. n one reported case of overdose, a 32 year old male with Darier's disease took 525 mg single dose. He vomited several hours later but experienced no other ill effects. No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg per day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men. No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured. Acitretin is a known human teratogen, and there is a very high risk of severe birth defects if a patient becomes pregnant while receiving acitretin or upon drug discontinuance (birth defects have been reported 2 years or longer after the last dose of acitretin). Teratogenicity generally is characterized by malformations involving craniofacial, cardiovascular, skeletal, and CNS structures. Acitretin was evaluated for mutagenic potential in unscheduled DNA synthesis assay in human fibroblasts. No evidence of mutagenicity of acitretin was observed in this assay. ANIMAL STUDIES: An 80-week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice. A carcinogenesis study of acitretin in rats, at doses up to 2 mg per kg per day administered 7 days per week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg per day). In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg per kg per day. Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays.
Liver test abnormalities occur in up to one third of patients on acitretin, although marked elevations above three times the upper limit of normal occur in only 1% to 5%. These abnormalities are typically transient, not accompanied by symptoms and can resolve even with continuation of acitretin, but they may be associated with mild symptoms and require drug discontinuation in up to 4% of patients.
Acitretin can also cause clinically apparent liver injury with symptoms and jaundice. Although uncommon, acute liver injury from acitretin is well described and is estimated to occur in 0.1% to 0.5% of treated patients. The onset of injury can be as soon as one week or up to 9 months after starting therapy. The pattern of liver enzyme elevations is typically hepatocellular (Case 1), but cholestatic hepatitis due to acitretin has been reported (Case 2). Most cases resolve rapidly with stopping acitretin. Rash, fever, eosinophilia and other signs of hypersensitivity occur in many but not all cases; autoantibodies are rare. The injury is not at all like that of vitamin A and is not associated with fat accumulation in stellate cells. Because its potential for causing hepatotoxicity, routine monitoring of serum aminotransferase levels during acitretin therapy is recommended.
Likelihood score, acitretin: B (likely rare cause of clinically apparent liver injury).
A similar pattern of acute liver injury was reported with etretinate, a related retinoid that was previously used for psoriasis and acne, but was withdrawn from use in the United States in 1998.
Likelihood score, etretinate: B (highly likely cause of clinically apparent liver injury).
Oral absorption of acitretin is optimal when given with food, and is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects.
Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%).
/MILK/ Retinoid transfer into breast milk was studied in a psoriatric woman receiving oral acitretin at a dosage of 40 mg once daily. Concentrations of the parent compound and its main metabolite, 13-cis acitretin, were measured in serum and mature milk during the initial nine days of therapy, using reverse-phase high performance liquid chromatography. At steady-state, trace amounts of the drug and metabolite (30-40 ng/mL) appeared in breast milk corresponding to a milk/serum concentration ratio of about 0.18. Acitretin was almost exclusively distributed in the fatty layers of the milk. Although the estimated amount of the drug consumed by a suckling infant would correspond to only 1.5% of the maternal dose, the toxic potential of acitretin justifies its avoidance in breast-feeding women.
Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following trials. After administration of a single 50-mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng per mL (mean: 416 ng per mL) and were achieved in 2 to 5 hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range: 47% to 109%) of the administered dose was absorbed after a single 50-mg dose of acitretin was given to 12 healthy subjects.
[EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
申请人：GALAPAGOS NV
公开号：WO2017012647A1
公开（公告）日：2017-01-26
The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.
[EN] FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLE CONDENSÉS UTILISÉS EN TANT QU'INHIBITEURS DE JAK
申请人：ALMIRALL SA
公开号：WO2017220431A1
公开（公告）日：2017-12-28
Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
The present invention relates to compounds of formula (I)
or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R
1
, R
2
, R
3
, R
4
, R
5
, R
5a
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
[EN] AZOLE COMPOUNDS AS PIM INHIBITORS<br/>[FR] COMPOSÉS D'AZOLE UTILISÉS EN TANT QU'INHIBITEURS DES PIM
申请人：AMGEN INC
公开号：WO2012129338A1
公开（公告）日：2012-09-27
The invention relates to bicyclic compounds of formulas I and Ia, and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.
